Project Summary/Abstract Despite therapeutic advances, no current treatment fully reverses impaired heart function. Heart failure often develops in individuals with coronary artery disease; high blood pressure or have suffered a myocardial infarc- tion. Heart failure can develop at any age, but increases in prevalence with age. Moreover, individuals of ad- vanced age also develop a syndrome of heart failure with preserved ejection fraction (HFpEF). Experimental models of aging as well as human studies suggest that endogenous repair capabilities become depleted with age. Therefore, novel interventions that preserve cardiac homeostasis are essential to reduce heart failure as- sociated morbidity and mortality. Our novel and potent family of synthetic peptide analogues of Growth Hor- mone Releasing Hormone (GHRH) receptor agonists (GHRH-As) produce a comprehensive repair program in two models of heart failure associated with ischemic heart disease. Treatment with GHRH-A improved cardiac function and attenuated remodeling in both acute and chronic models of ischemic injury, and improved periph- eral vascular function. These effects are mediated by direct activation of GHRH receptor signaling, promoting endogenous cell survival and repair mechanisms. However, the cellular targets and mechanisms involved re- main to be elucidated. The long-term goal of this proposal is to identify the mechanisms underlying GHRH- mediated cardiac protection and apply GHRH-targeted therapeutics to prevent HFpEF. We propose a combi- nation of in vivo and ex vivo approaches to test the central hypothesis that activation of GHRHR signaling re- stores cardiac structure and function in HFpEF by promoting cardiomyocyte proliferation and reducing fibrosis and apoptosis. The specific aims of this grant are to test the hypotheses that 1) GHRH Receptor signaling reg- ulates cardiomyocyte function; 2) GHRH-A therapy prevents cardiovascular changes and/or restores cardio- vascular function in Ang II-induced mouse models of HFpEF; and 3) GHRH-As prevent and/or reverse HFpEF in a porcine model of chronic kidney disease. Together this series of aims will provide novel insights into the mechanisms by which GHRH-As are cardioprotective and to the development of novel and effective therapeu- tic approaches tailored to improve cardiac performance in patients with HFpEF and other cardiovascular dis- eases.